Brain mechanisms in pain regulation

Abstract: The subjective sensitivity to pain differs greatly between individuals and neuroimaging has contributed to the understanding of the cerebral mechanisms involved in pain regulation. The descending pain inhibitory circuitry is a well defined cerebral network that enables regulation of afferent nociceptive information. The aim of this thesis was to investigate different aspects of pain modulation in patients with Fibromyalgia (FM) as well as the impact of specific genetic variations on pain sensitivity dynamics in healthy subjects. Study I demonstrated that patients with FM had an impaired mechanism for descending pain inhibition and that this deficiency was paired with a diminished activation of the rostral anterior cingulate cortex and the brainstem, two regions that play an important role in descending pain regulation. These results advance the understanding of the pathophysiology in FM and provide new directions for the development of effective treatments. Study II investigated the possible impact of negative mood on pain processing in patients with FM and found that brain activity during experimental pain was not modulated by depressive symptoms, anxiety, or catastrophizing thoughts. The activity of the brain regions previously implicated in the pathophysiology of FM were not correlated with high ratings of negative mood which suggests that there are two segregated cerebral mechanisms dealing with pain and negative mood in FM. In study III patients with FM were treated with a Noradrenaline-Serotonin Reuptake Inhibitor (milnacipran) or placebo for 12 weeks. All patients that reported an improvement of symptoms after treatment, including both milnacipran and placebo responders, were compared and results revealed that sensitivity to pressure improved selectively in milnacipran responders. This decreased sensitivity also correlated to the improvement of ongoing clinical pain. The study suggests that the specific effect of milnacipran acts through direct antinociceptive effects and/or by the strengthening of the endogenous pain inhibitory mechanisms. In study IV the genetic influence on the descending pain inhibitory function in healthy subjects was assessed. Results demonstrate that a genetic polymorphism (COMTval158met) with influence on the function of the noradrenergic and dopaminergic systems, is related to the response dynamics of repeated pain stimulations following opioid administration. Results suggest that the initial pain response is not influenced by the COMTval158met polymorphism but when the system is challenged the difference is expressed.